The ultimate goal of this proposal is to define the etiology of high-grade lymphma in the setting of HIV-infection, by looking at the specific hypothesis that EBY-induced chronic B-lymphocytic stimulation, in the setting of altered immune function (induced by HIV and/or other factors) may lead to unregulated B-cell proliferation, specific chromosomal translocation (t(8;14 on 8;22), c-myc activation, and subsequent development of monoclonal; B-cell lymphome. A population-based case control study design will be employed, in which cases and control are identified by the Cancer Surveillance Program (CSP), a population-based cancer registry for Los Angeles County. Cases with HIV-positive high-grade lymphoma (N=200) will be compared to two control groups: Group #1 controls will be HIV-positive patients with AIDS, who do not have lymphoma (N=200), while Group #2 controls will be HIV-negative patients with high-grade lymphoma (N=100). Epidemiologic questionnaires will be administered to all cases and controls, as will HIV and EBV antibody testing. A subgroup of cases (N=100) and control group #2 (N=50), who have been selected from the full CSP-based cohort on the basis of their initial diagnosis at the LA County-USC Medical Center, will be studied more carefully at the tissue level, for the various biologic correlates consistent with the hypothesis to be tested. An attempt will be made to correlate the epidemiologic variables identified in cases and controls with these biologic measures. Specially, we will determine: (1) if EBV genome is present, and to what extent, in peripheral blood lymphocytes and lymphoma tissues from cases versus controls (2) if HIV provirus is present, and expressed within lymphoma tissues from cases versus controls, using gene amplification and in situ hybridization; (3) the molecular genotype of HIV + and HIV - lymphomas by cytogenetic and molecular genetic analyses; and (4) if monoclonality of lymphoma tissue will differentiate cases from group #2 controls, by means of kappa/lambda immunophyenotype and immunoglobulin gene re-arrangement. The secondary aim of the proposal is to establish a serum and tissue band from these cases and controls, for use in future studies.